1. Field of the Invention
The invention relates to compounds effective in modulating cellular responses stimulated by ceramide-mediated signal transduction, in particular in response to stimulus by the cytokine tumor necrosis factor .alpha. (TNF-.alpha.). More specifically, it relates to compounds which inhibit the development of conditions associated with cell stimulus through the ceramide-mediated signal transduction pathway.
2. History of the Prior Art
The sphingomyelin pathway is a cellular signal transduction pathway that is believed to be involved in mediating cellular responses to several cytokines (including TNF-.alpha. and IL-I.beta.) and growth factors (e.g., platelet derived growth factor and fibroblast growth factor) (see, e.g., Dressier, et al., Science, 259:1715-1718, 1992; and, Jacobs and Kester, Amer.J.Physiol., 265: 740-747, 1993). It is believed that interaction of such molecules with cell surface receptors triggers activation of a plasma membrane sphingomyelinase. Sphingomyelinase in turn catalyzes the hydrolysis of sphingomyelin to ceramide and phosphocholine. Ceramide is believed to act as a second messenger through activation of a proline-directed, serine/threonine kinase (ceramide-activated protein kinase or "CaPK"). Ceramide also interacts with MAP kinase and protein kinase C zeta (see, e.g., Rivas, et al., Blood, 83:2191-2197, 1993) and with a serine/threonine protein phosphatase (see, Hannun, et al., TIBS, 20:73-77, 1995).
Recent investigation has provided evidence that the sphingomyelin pathway may mediate cellular senescence and apoptosis (programmed cell death) in response to TNF-.alpha. (see, e.g., Jayadev, et al., J.Biol.Chem., 270:2047-2052, 1994; and, Dbaibo, et al., J.Biol.Chem., 268:17762-17766, 1993) and radiation (Haimovitz-Friedman, et al., J.Exp.Med., 180:525-535, 1994). In this respect, ceramide has been presumed to mimic the effects of TNF-.alpha. on intracellular processes.